In 2016, the Apicomplexan Molecular Physiology Section examined the molecular basis of nutrient and ion uptake by PSAC and the potential for development of antimalarial therapies targeting this channel. We previously determined that PSAC inhibitors are less effective against uptake of certain solutes. Here, we designed and executed a high-throughput screen to identify a novel class of PSAC inhibitors that overcome this solute-inhibitor interaction. The new inhibitors differ from existing blockers and have distinct effects on channel-mediated transport, supporting a model of two separate routes for permeation though PSAC. Combinations of inhibitors specific for the two routes had strong synergistic action against in vitro parasite propagation, whereas combinations acting on a single route produced only additive effects. The magnitude of synergism depended on external nutrient concentrations, consistent with an essential role of the channel in parasite nutrient acquisition. The identified inhibitors will enable a better understanding of the channel's structure-function and may be starting points for novel combination therapies that produce synergistic parasite killing. These studies further validate PSAC as an essential and unexplored target for antimalarial development. PLoS ONE 11(2):e0149214 (2016).